Mucosal organs such as the intestine are highly vascular organs with extensive metabolic demands. Epithelial cells which line the intestine function to orchestrate a multitude of mucosal responses, and given their anatomic location, are primary targets for diminished blood flow and resultant tissue hypoxia. Our previous studies have explored the response of intestinal epithelial cells to hypoxia and these studies defined a transcriptional signaling pathway mediated by hypoxia-inducible factor (HIF). Activation of HIF results in the coordinated induction of a cluster of apically-localized, barrier protective gene products. Such induction parallels the accumulation of polymorphonuclear leukocytes (PMN, neutrophils). In this proposal, we will test the hypothesis that HIF coordinates protective epithelial responses to hypoxia. Three specific aims are proposed to test this hypothesis. First, we will elucidate the role of PMN to "inflammatory hypoxia" using in vitro and in vivo models of intestinal inflammation. Second, we will build on recent findings to further explore the role of HIF signaling to intestinal inflammation. In particular, we will define the contribution of HIF-1 and HIF-2 to protection afforded by inflammatory hypoxia. Third, we will extend our recent findings with pharmacological approaches that activate HIF (prolyl-hydroxylase inhibitors) to define specific targets and mechanisms of protection in both chemically- and genetically-induced murine models of intestinal inflammation. The overall aim of this proposal is to elucidate the how hypoxia and inflammation coordinately influence disease outcomes at the mucosal interface. PUBLIC HEALTH RELEVANCE: These studies are proposed to better understand basic mechanisms of inflammation in the intestine. Specifically, these studies will define how metabolic shifts present during episodes of inflammation might be harnessed to develop novel therapies for mucosal diseases. It is our hope that extensions of this work in human patients might impact inflammatory disease outcomes.